Tamoxifen is used as anti-cancerous drug. Here is brief introduction of it.

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2. TAMOXIFEN
Sadia Alvi
2013-Mphil-2282
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3. CONTENTS
History
Introducing Tamoxifen
Approved Indications
Pharmacokinetics
Pharmacodynamics
Effect of Drug on Body Systems
Special Population Study
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4. HISTORY
 Originally marketed as a an antifertility drug
and developed in the cornerstone treatment for
breast cancer.
 Approved by the FDA for postmenopausal
metastatic breast cancer in 1977
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5. INTRODUCING TAMOXIFEN
General Use
Breast cancer treatment
and prevention
Proper Name
Tamoxifen Citrate
Chemical Formula
C26H29NO
Chemical Type
non-steroidal Selective Estrogen Receptor Modulator (SERM)
Formulation
Tamoxifen is a fine white powder and delivered orally in pill form
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6. APPROVED INDICATIONS
Indication Year of Approval
Metastatic Breast Cancer (postmenopausal) 1977
Adjuvant Breast Cancer (postmenopausal, node-positive) 1986
Metastatic Breast Cancer (premenopausal) 1989
Adjuvant Breast Cancer (postoperative and/or chemotherapy
treatment, postmenopausal, node-negative)
1990
Metastatic Breast Cancer (male) 1993
Reduction in Breast Cancer Incidence 1998
Ductal Carcinoma in Situ (DCIS) 2000
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7. PHARMACOKINETICS
Absorption Distribution Metabolism Excretion
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8. ABSORPTION
20 mg Tamoxifen Oral Dose
Cmax 40 ng/mL
tmax 5 hours
Terminal t1/2 5 -7 days
Bioavailability 89%
Steady State
1 dose/day
3 months
122 ng/mL
0
5
10
15
20
25
30
35
40
45
0 1 2 3 4 5 10 20 30 40 50 60 70 80 90 100 110 120
DrugConcentration(ng/mL)
Time (h)
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9. DISTRIBUTION
 Tamoxifen is 99% albumin-bound
in serum
 Volume of Distribution
 50 – 60 L/Kg
 This represents an extensive
distribution to the peripheral
tissues
 Areas of high concentration
 Breast
 Lung
 Liver
 Brain
 Bone
 Uterus
http://www.sciencephoto.com/media/257869/enlarge
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10. METABOLISM
 Tamoxifen undergoes first-
pass metabolism
 Tamoxifen is metabolized
by CYP enzymes
 CYP3A
 CYP2C9
 CYP2D6
 Tamoxifen undergoes
enterohepatic circulation
 Prolongation of blood
levels and fecal excretion
Liver
CYP-450
GI Tract
Renal Excretion
Tamoxifen
Enterohepatic
circulation
Biliary Excretion
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11. METABOLISM
 Extensive metabolism
following absorption
 Demethylation
 Hydroxylation
 Conjugation
 3 major metabolites
are produced
 N-desmethyl tamoxifen
 4-hydroxy tamoxifen
 4-hydroxy-N-desmethyl
tamoxifen (endoxifen)
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12. EXCRETION
 Primary route of elimination
 Biliary excretion
 65% of administered drug is excreted slowly over a 2
week period
 Secondary route of elimination
 Renal excretion
 Less than 1% excreted via urine
 Excreted drug properties
 70% are polar conjugates
 Indicates high level of metabolism
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13. PHARMACODYNAMICS
 Estrogen receptors (ER)
exist in different tissues
 Breast, brain, lung, liver,
bone, uterus
 Normal Cellular Function
 Estrogen binds to ER
 Transcription factor
synthesis
 Cell proliferation
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14. PHARMACODYNAMICS
 Selective Estrogen Receptor
Modulator (SERM)
 A drug that targets estrogen
receptors in specific tissues
 How Tamoxifen Works
 Antagonist in breast and
brain
 No transcription
 Cell growth arrest/apoptosis
 Agonist in lung, liver, bone,
and uterus
 Normal function
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15. EFFECT OF DRUG ON BODY SYSTEMS
 Tamoxifen also binds and
inhibits
 Protein Kinase C
 Regulates cell growth and
differentiation
 Calmodulin
 Mediates process such as
metabolism
 P-glycoproteins
 Efflux pump
 Ca2+ Channels
 Signal transduction
Tamoxifen can target mutated cancer cells that lack ER
Tamoxifen
Cell membrane fluidity
Calmodulin
PKC
DNA
ER
transcription
Apoptosis
x
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16. EFFECT OF DRUG ON BODY SYSTEMS
 Most common side
effects (up to 25%
occurrence)
 Rarely severe enough to
require discontinuation
of treatment
 Hot flashes
 Nausea
 Vomiting
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17. EFFECT OF DRUG ON BODY SYSTEMS
ADVERSE DRUG REACTIONS BENEFITS OF DRUG
 Increased risk of uterine
cancer
 Agonist in uterine ER
 Increased cell proliferation
 Increased risk of blood
clot formation
 Increase in clotting factors
 Increased risk of cataract
 Ophthalmic toxicities
 Reduced risk of
breast cancer
 ER Antagonist
 Strengthens bones
 ER Agonist
 Lower risk of heart
disease
 Increase HDL cholesterol
 Reduce LDL cholesterol
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18. EFFECT OF DRUG ON BODY SYSTEMS
 Drug-Drug Interactions
 Coumarin-type anticoagulants (Warfarin)
 Both 99% bound to albumin
 Tamoxifen has a higher affinity for albumin
 Co-administration results in a risk of Warfarin over dose
 Rifampin (TB Antibiotic)
 CYP 34A inducer
 Reduces Tamoxifen’s
 Bioavailability by 86%
 Cmax by 55%
 Prozac (Anti-depressant)
 CYP 2D6 competitor
 Decreases the effect of Tamoxifen
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19. SPECIAL POPULATION STUDY
Brain cancer patients
New Indication
Treatment for malignant glioma
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20. ABOUT THE POPULATION
 Rational for Special Population
 High level of cell proliferation in
brain
 Brain cells contain estrogen
receptors
 Proliferative signal transduction
in glioma cells has been shown to
occur through a predominantly
Protein Kinase C dependent
pathway
 P-glycoprotein functions as a
transporter in the blood-brain
barrier
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21. PHARMACOKINETICS
Absorption
Oral absorption through the
portal vein into the liver
Excretion
Biliary system
Metabolism
First pass metabolism
CYP 450 enzymes
Distribution
Tissues expressing ER,
including the brain
ADME
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22. PHARMACODYNAMICS
 Tamoxifen is an ER antagonist in the brain
 Prevents transcription
 Cell growth arrest/apoptosis
 Tamoxifen is the only PKC inhibitor small
enough to cross the blood-brain barrier
 Inhibits signal transduction
 Cell growth arrest/apoptosis
 Tamoxifen inhibits P-glycoprotein function
 Increased bioavailability of Tamoxifen
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23. REFERENCES
 Avastin (bevacizumab) injection, solution [Genetech, Inc.]. US NLM, NIH, HHS.
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 Clinical Trials: Tamoxifen. US NLM, NIH, HHS.
<http://clinicaltrials.gov/ct2/results?term=tamoxifen>
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Ford L., and Wolmark N. 1998. Tamoxifen for prevention of breast cancer: report
of the national surgical adjuvant breast and bowel project p-1 study. Journal of the
National Cancer Institute. 90 (18). 1371-1388
 Kleinsmith L.J., Kerrigan D., and Kelly J. 2010. Understanding cancer and related
topics: understanding esrogen receptors, tamoxifen, and raloxifene. National
Cancer Institute.
 The Merck Index. 13th Edition. Merck & Co., INC. Whitehouse Station, NJ. 2001.
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24. REFERENCES
 Lien E.A., Solheim E., and Ueland P.M. 1991. Distribution of tamoxifen and its
metabolites in rat and human tissues during steady-state treatment. Cancer
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 Mackay H.J. and Twelves C.J. 2003. Protein kinase C: a target for anticancer
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 Nolvadex (tamoxifen citrate) Tablet [AstraZeneca Pharmaceuticals LP]. US NLM,
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<http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3420>
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25. REFERENCES
 Schroth W., Goetz M.P., Hamann U., Fasching P.A., Schmidt M., Winter S., Fritz P.,
Simon W., Suman V.J., Ames M.M., Safgren S.L., Kuffel M.J., Ulmer H.U., Strick R.,
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M., and Brauch H. 2009. Association between CYP2D6 polymorphisms and
outcomes among women with early stage breast cancer treated with tamoxifen.
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 Ramachandran C., Khatib Z., Pefkarou A., Fort J., Fonseca H.B., Melnick S.J., and
Escalion E. 2004. Tamoxifen modulation of etoposide sytotoxicity involves inhibition
of protein kinase C activity and insulin-like growth factor II expression in brain tumor
cells. Journal of Neuro-Oncology. 67. 19-28
 Couldwell W.T., Hinton D.R., Surnock A.A., DeGiorgio C.M., Weiner L.P., Apuzzo M.L.J.,
Masri L., Law R.E., and Weiss M.H. 1996. Treatment of recurrent malignant gliomas
with chronic oral high-dose tamoxifen. Clinical Cancer Research. 2. 619-622
 Mandlekar S. and Kong A.N.T. 2001. Mechanisms of Tamoxifen – Induced
apoptosis. Apoptosis. 6. 469-477.
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